Adenosine has numerous physiological roles, including, inter alia, modulator of vasodilation and hypotension, muscle relaxant, central depressant, inhibitor of platelet aggregation, regulator of energy supply/demand, and responder to oxygen availability. Bruns, Nucleosides & Nucleotides, 10(5), 931-943 (1991). These roles are mediated by at least two classes of extracellular receptors, named A.sub.1 and A.sub.2. The A.sub.1 receptors are usually found on the working cells of a tissue (e.g., neurons and cardiomyocytes) and mediate decreases in oxygen demand. The A.sub.2 receptors, often located on vascular elements, mediate response to oxygen supply. The activation of A.sub.1 and A.sub.2 receptors by adenosine, adenosine analogues, or nonselective adenosine agonists results in an increase in tissue oxygen supply (or a decrease in oxygen demand) and a return to energy supply/demand balance. Bruns, supra.
Because of its potent actions on many organs and systems, adenosine and its receptors have been the subject of considerable drug-development research. Daly, J. Med. Chem., 25, 197 (1982). Potential therapeutic applications for agonists include, for instance, the prevention of reperfusion injury after cardiac ischemia or stroke, and treatment of hypertension and epilepsy. Jacobson, et al., J. Med. Chem., 35, 407-422 (1992). Adenosine itself has recently been approved for the treatment of paroxysmal supraventricular tachycardia. Pantely, et al., Circulation, 82, 1854 (1990).
A problem encountered in animal and clinical trials of adenosine agonists has been that deleterious side-effects (such as intense behavioral effects) have been noted even when using low dosages, thereby lessening the compounds' therapeutic use. Snyder, et al., Proc. Nat'l. Acad. Sci. U.S.A., 78, 3260-3264 (1981); Nikodijevic, et al., FEBS Letters, 261, 67-70 (1990) (hereinafter "Nikodijevic 1990"); Nikodijevic, et al., J. Pharm. Exp. Therap., 259, 286-294 (1991); Durcan, et al., Pharmacol. Biochem. Behav., 32, 487-490 (1989). For example, peripherally administered N.sup.6 -substituted adenosine analogs, such as N.sup.6 -cyclohexyl adenosine, elicit locomotor depression. This phenomenon is generally interpreted as a central nervous system effect because very low agonist doses are effective, and peripherally-selective (in other words, not selective for the central nervous system) antagonists are inactive in reversing this depression. In contrast, non-selective antagonists (e.g., xanthines such as caffeine or theophylline), which freely cross the blood-brain barrier, reverse adenosine-agonist-induced behavioral depression. Nikodijevic 1990, supra.
It has been shown that certain adenosine agonists protect against ischemia-induced brain degeneration. These agonists are selective for one sub-class of adenosine receptors, known as A.sub.1 receptors. The mode of protection is believed to be modulation of excitatory amino acid toxicity in the central nervous system. Evans, et al., Neurosc. Lett., 83, 287-92 (1987); von Lubitz, et al., J. Mol. Neurosci., 2, 53-59 (1990). This class of agonist adenosine analogs, however, also displays the deleterious behavioral effects.
A useful class of agonists, not hitherto discovered, would have the characteristic of not crossing the blood-brain barrier, thereby avoiding the undesirable behavioral effects, yet still be able to approximate adenosine's beneficial characteristics in protecting against cardiac ischemia or hypoxia in general.
The present invention addresses such a class of adenosine agonists. In particular, the present invention relates to the oxygen-related activities of adenosine and discloses hitherto unknown adenosine analogs that act analogously to adenosine in its oxygen-related activities. Unlike adenosine and other known analogs that are incapable of being excluded by the blood-brain barrier, the compounds of the present invention are excluded by the blood-brain barrier and retain potency.